Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs

Nature Immunology volume 12, pages 327–334 (2011)Cite this article

Subjects

Abstract

Interleukin (IL)-10 is an important regulatory cytokine that can modulate excessive immune mediated injury. Several distinct cell types have been demonstrated to produce IL-10, including most recently CD8+ cytotoxic T lymphocytes (CTLs) responding to respiratory virus infection. Here we report that CD4+ T cell help in the form of IL-2 is required for IL-10 production by CTLs, but not for the induction of CTL effector cytokines. We show that IL-2 derived from CD4+ helper T cells cooperates with innate immune cell–derived IL-27 to amplify IL-10 production by CTLs through a Blimp-1-dependent mechanism. These findings reveal a previously unrecognized pathway that coordinates signals derived from innate and helper T cells to control the production of a regulatory cytokine by CTLs during acute viral infection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Induction of IL-10-producing CTLs in vivo requires IL-27 and CD4+ T cells.
Figure 2: CD4+ T cell help is selectively required for the induction of IL-10-producing CTLs in vivo.
Figure 3: IL-2 provides the help from CD4+ T cell to CTLs for IL-10 production in vitro.
Figure 4: IL-2 is required for the induction IL-10-producing CTLs in vivo.
Figure 5: IL-2 and IL-27 synergistically induce IL-10 production by both mouse and human CTLs.
Figure 6: Induction of IL-10-producing CTLs by IL-2 and IL-27 is Blimp-1 dependent.
Figure 7: Blimp-1 deficiency in T cells results in diminished IL-10 production and enhanced pulmonary inflammation.

Similar content being viewed by others

References

  1. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  Google Scholar 

  2. Couper, K.N., Blount, D.G. & Riley, E.M. IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).

    Article  CAS  Google Scholar 

  3. Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

    Article  CAS  Google Scholar 

  4. Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D. CD4+CD25-Foxp3- Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007).

    Article  CAS  Google Scholar 

  5. Jankovic, D. et al. Conventional T-bet+Foxp3- Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

    Article  CAS  Google Scholar 

  6. Sun, J., Madan, R., Karp, C.L. & Braciale, T.J. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat. Med. 15, 277–284 (2009).

    Article  CAS  Google Scholar 

  7. O'Garra, A. & Vieira, P. TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).

    Article  CAS  Google Scholar 

  8. Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    Article  CAS  Google Scholar 

  9. Maynard, C.L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat. Immunol. 8, 931–941 (2007).

    Article  CAS  Google Scholar 

  10. Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183, 797–801 (2009).

    Article  CAS  Google Scholar 

  11. Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).

    Article  CAS  Google Scholar 

  12. Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).

    Article  CAS  Google Scholar 

  13. Fitzgerald, D.C. et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat. Immunol. 8, 1372–1379 (2007).

    Article  CAS  Google Scholar 

  14. Stumhofer, J.S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

    Article  CAS  Google Scholar 

  15. Jankovic, D. & Trinchieri, G. IL-10 or not IL-10: that is the question. Nat. Immunol. 8, 1281–1283 (2007).

    Article  CAS  Google Scholar 

  16. Spolski, R., Kim, H.P., Zhu, W., Levy, D.E. & Leonard, W.J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol. 182, 2859–2867 (2009).

    Article  CAS  Google Scholar 

  17. Saraiva, M. et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209–219 (2009).

    Article  CAS  Google Scholar 

  18. Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    Article  CAS  Google Scholar 

  19. Belz, G.T., Wodarz, D., Diaz, G., Nowak, M.A. & Doherty, P.C. Compromised influenza virus-specific CD8(+)-T-cell memory in CD4+-T-cell-deficient mice. J. Virol. 76, 12388–12393 (2002).

    Article  CAS  Google Scholar 

  20. Johnson, S. et al. Selected Toll-like receptor ligands and viruses promote helper-independent cytotoxic T cell priming by upregulating CD40L on dendritic cells. Immunity 30, 218–227 (2009).

    Article  CAS  Google Scholar 

  21. Madan, R. et al. Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J. Immunol. 183, 2312–2320 (2009).

    Article  CAS  Google Scholar 

  22. Stetson, D.B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003).

    Article  CAS  Google Scholar 

  23. Malek, T.R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).

    Article  CAS  Google Scholar 

  24. Belz, G.T. & Masson, F. Interleukin-2 tickles T cell memory. Immunity 32, 7–9 (2010).

    Article  CAS  Google Scholar 

  25. Gong, D. & Malek, T.R. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J. Immunol. 178, 242–252 (2007).

    Article  CAS  Google Scholar 

  26. Martins, G.A. et al. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 (2006).

    Article  CAS  Google Scholar 

  27. Sun, J.C., Williams, M.A. & Bevan, M.J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 5, 927–933 (2004).

    Article  CAS  Google Scholar 

  28. Sun, J.C. & Bevan, M.J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003).

    Article  CAS  Google Scholar 

  29. Shedlock, D.J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003).

    Article  CAS  Google Scholar 

  30. Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009).

    Article  CAS  Google Scholar 

  31. Keene, J.A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 (1982).

    Article  CAS  Google Scholar 

  32. Bennett, S.R., Carbone, F.R., Karamalis, F., Miller, J.F. & Heath, W.R. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J. Exp. Med. 186, 65–70 (1997).

    Article  CAS  Google Scholar 

  33. Zhang, S., Zhang, H. & Zhao, J. The role of CD4 T cell help for CD8 CTL activation. Biochem. Biophys. Res. Commun. 384, 405–408 (2009).

    Article  CAS  Google Scholar 

  34. Pipkin, M.E. et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79–90 (2010).

    Article  CAS  Google Scholar 

  35. Kalia, V. et al. Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32, 91–103 (2010).

    Article  CAS  Google Scholar 

  36. Kohlmeier, J.E., Cookenham, T., Roberts, A.D., Miller, S.C. & Woodland, D.L. Type I interferons regulate cytolytic activity of memory CD8+ T cells in the lung airways during respiratory virus challenge. Immunity 33, 96–105 (2010).

    Article  CAS  Google Scholar 

  37. Stumhofer, J.S. & Hunter, C.A. Advances in understanding the anti-inflammatory properties of IL-27. Immunol. Lett. 117, 123–130 (2008).

    Article  CAS  Google Scholar 

  38. Yoshida, H., Nakaya, M. & Miyazaki, Y. Interleukin 27: a double-edged sword for offense and defense. J. Leukoc. Biol. 86, 1295–1303 (2009).

    Article  CAS  Google Scholar 

  39. Crotty, S., Johnston, R.J. & Schoenberger, S.P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11, 114–120 (2010).

    Article  CAS  Google Scholar 

  40. Kallies, A., Xin, A., Belz, G.T. & Nutt, S.L. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity 31, 283–295 (2009).

    Article  CAS  Google Scholar 

  41. Shin, H. et al. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31, 309–320 (2009).

    Article  CAS  Google Scholar 

  42. Lawrence, C.W. & Braciale, T.J. Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection. J. Immunol. 173, 1209–1218 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the rest of Braciale laboratory for critical comments and B. Small for excellent technical assistance. We thank C.L. Karp (Cincinnati Children's Hospital Medical Center), M. Mohrs (Trudeau Institute), W. Leonard (US National Institutes of Health) and T.R. Malek (University of Miami) for reagents. This work was supported by the US National Institutes of Health (grants AI-15608, HL-33391, AI-37293 and U19 AI-083024 to T.J.B.), University of Virginia Center for Immunity, Inflammation and Regenerative Medicine start-up funds to R.S. and an American Lung Association Postdoctoral Fellowship (RN-123000) to J.S.

Author information

Authors and Affiliations

  1. The Beirne B. Carter Center for Immunology Research, The University of Virginia, Charlottesville, Virginia, USA

    Jie Sun, Haley Dodd, Emily K Moser & Thomas J Braciale

  2. Department of Pathology, The University of Virginia, Charlottesville, Virginia, USA

    Jie Sun & Thomas J Braciale

  3. Department of Medicine, The University of Virginia, Charlottesville, Virginia, USA

    Rahul Sharma

  4. Department of Microbiology, The University of Virginia, Charlottesville, Virginia, USA

    Thomas J Braciale

Authors
  1. Jie Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haley Dodd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emily K Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahul Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas J Braciale
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S. designed the project, performed most of the experimental work, analyzed the data and wrote the manuscript. H.D. and E.K.M. performed some of the quantitative RT-PCR and ELISA experiments. R.S. contributed to reagents and suggestions. T.J.B. supervised the project, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Thomas J Braciale.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–22 (PDF 2015 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, J., Dodd, H., Moser, E. et al. CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol 12, 327–334 (2011). https://doi.org/10.1038/ni.1996

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1996

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing